This invention relates generally to portable devices and methods useful for optimizing the diameter distribution of a medical aerosol, and reducing the amount of variability arising from variations in ambient conditions. More specifically, this invention relates to portable devices for controlling the temperature of air to be mixed with aerosol particles of drugs to be delivered to the lung.
There are several known methods for the aerosolized delivery of drugs. In general, the methods include: (1) placing an aqueous formulation within a nebulizer device which by various mechanical means causes the drug formulation to be aerosolized in a continuous stream which is inhaled by the patient; (2) dry powder inhalers which create a fine powder of the drug and aerosolize the powder in a dust form which is inhaled; (3) metered dose inhalers which dissolve or disperse the drug in a low boiling point propellant; and (4) more current devices such as that disclosed within U.S. Pat. No. 5,660,166 issued Aug. 26, 1997 which force aqueous formulations through a nozzle to create an aerosol which is inhaled by the patient.
In accordance with each of the known methods for aerosolizing a drug it is important to produce an aerosol which has particles within a desired diameter range, e.g. 0.5 to 12.0 microns and more preferably 1.0 to 3.5 microns. In addition to producing small particles it is preferable to produce particles which are relatively consistent in diameter, i.e. produce an aerosol wherein a large percentage of the particles fall within the desired diameter range. In addition, it is desirable to produce an aerosol which has the property that the key measures of aerosol quality, such as particle diameter and dose emitted are not effected by ambient conditions such as temperature and or relative humidity. With any of the known methods for aerosol delivery of drugs there are difficulties with respect to making the particles sufficiently small. Along with these difficulties there are difficulties with respect to creating particles which are relatively consistent in diameter. These difficulties are particularly acute when attempting to provide for systemic delivery of an aerosolized drug. Efficient systemic delivery requires that the aerosol be delivered deeply into the lung so that the drug can efficiently reach the air/blood exchange membranes in the lung and migrate into the circulatory system.
Aerosol delivery to the lungs has been used for delivery of medication for local therapy (Graeser and Rowe, Journal of Allergy 6:415 1935). The large surface area, thin epithelial layer, and highly vascularized nature of the peripheral lung (Taylor, Adv. Drug Deliv. Rev. 5:37 1990) also make it an attractive site for non-invasive systemic delivery. Unlike other avenues of non-invasive delivery such as trans-dermal, nasal, or buccal, the lung is designed as a portal of entry to the systemic circulation. However, targeting the peripheral lung requires careful control of the aerosol particle diameter and velocity distributions, in order to by pass the exquisitely evolved particle filtering and clearing functions of the bronchial airways.
Many authors have reported results of experiments or mathematical models showing that micron sized particles are required for delivery to the lungs (c.f. Stahlhofen, Gebhart and Heyder, Am. Ind. Hyg. Assoc. J. 41:385 1980, or Ferron, Kreyling and Haider, J. Aerosol Sci. 19:611 1987). One example is the model of the Task Group on Lung Dynamics (Morrow et. al. Health Physics 12:173 1966). As FIG. 1 shows, under the assumptions of this model, particles of diameter less than xcx9c3.5 xcexcm are required to avoid the oropharynx and bronchial airways. FIG. 1 might suggest that the maximum efficiency of deposition of drugs delivered to the pulmonary region of the lung is limited to xcx9c60%. However, as can be seen in FIG. 2, efficiencies approaching 100% can be achieved by allowing the particles to settle gravitationally during a ten second breath hold (Byron, J. Pharm. Sci. 75:433 1986).
It has been demonstrated that ambient conditions can strongly effect the amount of aerosol particles less than 3.5 xcexcm emitted from aerosol generation device. One example is the work of Phipps and Gonda (Chest 97:1327-1332, 1990) showing that the amount of aerosol less than 3.5 xcexcm delivered by an aerosol drug delivery device changed from 33% to 73% when the relative humidity changed from 100% to 70%. Similar work with a dry powder (Hickey et al J. Pharm. Sci. 79, 1009-1011) demonstrated a change in the amount of aerosol less than 3.5 xcexcm from 9% to 42% when the ambient relative humidity changed from 97% to 20%. These data are tabulated in Table 1.
A device useful for controlling the temperature of the air surrounding an aerosolized drug formulation is provided in U.S. Pat. No. 6,131,570, which issued on Oct. 17, 2000. An element is preheated prior to aerosolizing the drug formulation. After preheating has been accomplished, the drug formulation is aerosolized substantially contemporaneously with the control of air flow through a space in which the preheated element is contained, whereby heated air mixes with the aerosolized drug formulation, thereby evaporating liquid carrier from the aerosol particles to obtain smaller particles to be delivered to the lungs of the patient.
Since devices of this type are designed to be portable, primary goals include making the heating element as efficient as possible for performing the functions of rapidly heating up and storing energy during the preheat stage, as well as rapidly releasing heat to the air as it flows by the heating element to be delivered to the aerosolized drug. Efficient storing and releasing of heat energy are basically contradictory in nature, however, and these goals remain a problem to be addressed, since increasing the efficiency of these features allows a reduction in the size and weight of the power source which must necessarily be included in a portable device.
Many pharmaceutical compounds of a wide range of molecular weights are potential candidates for systemic delivery via the lung. Small molecules analgesics such as morphine or fentanyl could be delivered to pain patients, e.g. cancer or post-operative patients. Morphine has demonstrated bioavailability when delivered via the lung (S. J. Farr, J. A. Schuster, P. M. Lloyd, L. J. Lloyd, J. K. Okikawa, and R. M. Rubsamen. In R. N. Dalby, P. R. Byron, and S. J. Farr (eds.), Respiratory Drug Delivery V, Interpharm Press, Inc., Buffalo Grove, 1996, 175-185).
Potent peptide hormones are available for a variety of therapeutic indications. Leuprolide, for example, is a GnRH super-agonist useful in the treatment of endometriosis and prostate cancer. Leuprolide also has potential applications in the field of breast cancer management and the treatment of precocious puberty. Calcitonin enhances metabolism and may be a useful therapeutic agent for the management of osteoporosis, a common complication of aging.
To treat conditions or diseases of the endocrine system, pharmaceutical formulations containing potent peptide hormones are typically administered by injection. Because the stomach presents a highly acidic environment, oral preparations of peptides are unstable and readily hydrolyzed in the gastric environment. Currently, there are no oral preparations of therapeutic peptide agents commercially available.
Both calcitonin and leuprolide can be administered nasally. (See Rizzato et al., Curr. Ther. Res. 45:761-766, 1989.) Both drugs achieve blood levels when introduced into the nose from an aerosol spray device. However, experiments by Adjei et al. have shown that the bioavailability of leuprolide when administered intranasally is relatively low. However, an increase in the bioavailability of leuprolide can be obtained by administering the drug into the lung. Intrapulmonary administration of leuprolide has been shown to be an effective means of non-invasive administration of this drug (Adjei and Garren, Pharmaceutical Research, Vol. 7, No. 6, 1990).
Intrapulmonary administration of drugs has the advantage of utilizing the large surface area available for drug absorption presented by lung tissue. This large surface area means that a relatively small amount of drug comes into contact with each square centimeter of lung parenchyma. This fact reduces the potential for tissue irritation by the drug and drug formulation. Local irritation has been seen with nasal delivery of insulin and has been a problem for commercialization of nasal preparations of that drug. It is a problem with peptide hormones that they are very potent with effects that are not immediately manifested. For example, therapy with leuprolide for prostate cancer does not typically produce any acute clinical effects. Similarly, prophylaxis against osteoporosis with calcitonin will not produce any acute symptoms discernible to the patient. Therefore, administration of each dose of these drugs must be reliable and reproducible.
A portable, self-contained device useful for controlling the temperature of the air surrounding an aerosolized drug formulation is provided, as well as methods for more efficiently transferring heat energy to air which is thereby warmed and applied to the drug formulation. A method of dissipating power to store heat, and then releasing the stored heat to warm a bolus of air, and a device for carrying out such method are provided. Such a method includes supplying power from a portable power source to a heating element; storing heat in the heating element as power is supplied from the portable power source; determining when the heating element achieves a predetermined operating temperature; and flowing air over the heating element after the heating element has achieved the predetermined operating temperature, to release heat to the flowing air, whereby the thermal time constant of the device may be greater than about 10 seconds in still air, preferably greater than about 15 seconds, more preferably greater than about 20 seconds, still more preferably greater than about 30 seconds and most preferably greater than about 40 seconds, and the thermal constant of the device for releasing heat to the flowing air is less than about 15 seconds, more preferably less than about 7 seconds, even more preferably less than about 5 seconds.
During the preheat phase, as heat is stored in the heating element, it is noted that energy may be distributed within the heating element. For example, a primary element may be heated, and some or all of the heat generated may be distributed to a secondary element for storage.
The flowing air may be driven by inhalation by a user on a channel fluidly connected with the heating element. However, it would also be possible to construct a heating device employing some other driver for passing air over the heating element (such as an electric fan, for example) to warm the air in much the same manner that the inhaled air is warmed. The patient could subsequently inhale the evaporated drug from a holding chamber into which the fan blows the warmed air (which evaporates the drug and carries it to the holding chamber). The portable power source may comprise at least one battery cell with or without at least one capacitor, for example.
The present invention includes modifications of a heating device, and particularly heating element to increase the thermal time constant of the heating device in still air. Such modifications may include coating the thermal element with gold; providing a shield around the heating element and, optionally, one or more shield closing elements, to reflect radiant heat, mitigate losses from the heating element to the channel due to free convection, and to absorb some heat that would otherwise have been lost from the heating element during storing of heat, wherein the shield (and optionally, shield closing elements) function(s) as a secondary heat storage element that can subsequently release heat for warming the moving air; coating the shield and or shield closing elements with gold; and combinations thereof.
Modifications of a heating device to optimize the thermal time constant of the heating device in moving air are also disclosed. Such characteristics may include configuring one or more passive elements to absorb heat from and release heat to the moving air. The heating element may comprise a shape that enhances heat transfer in moving air.
Hand-held, portable air temperature controlling devices are disclosed which comprise a heating element adapted to receive energy from a self-contained, portable power source and store the energy as heat during a preheat operation; and a housing surrounding the heating element and defining an air flow path through which air flows over the heating element to transfer heat to the air during an air warming operation; wherein a thermal time constant of the heating device in still air during the preheat operation is greater than about 15 seconds and a thermal time constant of the heating device in moving air during the warming operation is less than about 15 seconds.
A shield may be provided to substantially surround the heating element, while remaining open at opposite ends to allow air to pass therethrough. Optionally, a shield closing element may be provided in one or each open end to further shield and surround the heating element during preheat, while allowing air flow therethrough during an air warming operation.
A passive element may be provided downstream of the heating element, wherein the passive element conditions a heat pulse generated when air flows over the heating element to transfer heat to the air during the air warming operation.
An air temperature controlling device is further disclosed as comprising a self-contained, portable power source adapted to connect with the heating (or thermal) element to supply power thereto.
In one example, a hand-held, portable air temperature controlling device comprises a heating element adapted to receive energy from a self-contained, portable power source and store the energy as heat during a preheat operation; and a housing surrounding the heating element and defining an air flow path through which air flows over the heating element to transfer heat to the air during an air warming operation; wherein the heating element comprises an electrically resistive ribbon having a thermal time constant in still air during the preheat operation which is greater than about 15 seconds and a thermal time constant in moving air during the warming operation which is less than about 15 seconds.
The resistive ribbon may be constructed of two banks, with each bank being configured into a series of narrow channels.
Further, a shield may be provided to substantially surround the resistive ribbon, while having open opposite ends to allow air to pass therethrough.
Still further, a shield closing element, such as a mesh element may be fitted in one or both of the open opposite ends of the shield.
The invention increases the number and types of pharmaceutical formulations which can be administered efficiently and reproducibly by inhalation. More particularly, the invention makes it possible to inhale formulations which are intended for systemic delivery, including peptides such as insulin and analogs of insulin (e.g., insulin lispro). This is done by increasing the reproducibility of dosing by adjusting particle diameter to a consistent level in different surrounding humidities. Further, particular areas of the lung are targeted by (1) including aerosolized formulation in precisely determined volumes of air, (2) warming air surrounding the aerosolized formulation so as to evaporate carrier and reduce the particle diameter and/or to prevent water vapor in the air from condensing on particles, (3) excluding aerosolized formulation from other volumes of air delivered to the lung in order to correctly position an aerosol. Further, the heating means can be used with any type of means of generating an aerosol. More specifically, the heating means can be used with a nebulizer, a dry powder inhaler or metered dose inhaler. However, the major benefits of the invention are obtained when used with a device which creates aerosolized particles by moving liquid (aqueous or ethanolic) formulations through small holes to create particles (see U.S. Pat. No. 5,718,222 issued Feb. 17, 1998). All types of nebulizers benefit from the invention by reducing variable effects caused by the environment, e.g., changes in humidity.
The amount of energy added can be adjusted depending on factors such as the desired particle diameter, the amount of the carrier to be evaporated, the water vapor content (humidity) and temperature of the surrounding air, the composition of the carrier, and the region of the lung targeted.
To obtain reproducible, efficient systemic delivery it is desirable to get the aerosolized formulation deeply into the lung. This requires the delivery of the formulation in aerosol particles of diameter less than approximately 3.5 xcexcm. Direct generation of particles in this diameter range can be difficult, due to the large ratio of surface area to volume of these small particles. Energy may be added in an amount sufficient to evaporate all or substantially all of the carrier from an aqueous aerosol and thereby provide particles of dry powdered drug or highly concentrated drug formulation to a patient which particles are (1) uniform in diameter regardless of the ambient humidity and temperature (2) preferably produced from a liquid formulation, and (3) smaller due to the evaporation of the carrier.
A primary object of the invention is to provide an air temperature controlling device comprised of a receptacle for holding a self-contained power source such as electric power cells forming a battery, a channel comprising an air flow path which includes an opening into which air can be inhaled and a second opening into which air is delivered and aerosol is generated, a heating element connected to the electrical contacts of the receptacle and positioned in a manner such that air flowing by the heating element flows through the channel, wherein the device is a hand-held, self-contained device having a total weight of one kilogram or less.
An important advantage of the invention is that the heating device can heat a sufficient amount of air so as to evaporate a sufficient amount of carrier on aerosolized particles to make the particles consistent in diameter and sufficiently small as to improve the repeatability and efficiency of drug delivery.
It is an object of this invention to provide a portable air temperature controlling device able to warm the air which will interact with particles of an aerosolized drug formulation.
It is a further object of the invention to provide a drug delivery device containing such a heating element which is heated by a portable, self-contained energy source.
It is a further object of the invention to provide methods of administering aerosolized drug formulations in which the air, interacting with or to interact with the aerosolized formulation, is warmed using a portable air temperature controlling device.
An advantage of the present invention is that it can be used for ambulatory patients.
Another object of the invention is that it makes it possible to adjust particle diameter by adding energy to the air surrounding the particles in an amount sufficient to evaporate carrier and reduce total particle diameter.
Another object of the invention is that it reduces or eliminates the variability in particle diameter due to variations in ambient relative humidity and temperature by ensuring that the delivered particles are in the range of 1-3.5 xcexcm independent of ambient conditions. This object of the invention can apply equally well to aerosol generation devices that generate aerosols of liquid solutions of drug, liquid suspensions of drug, or dry powders of drug.
Another object is to provide a device for the delivery of aerosols which measures ambient humidity via a solid state hygrometer, and/or measures ambient temperature via a temperature sensor.
A feature of the invention is that drug can be dispersed or dissolved in a liquid carrier such as water and dispersed to a patient as dry or substantially dry particles.
These and other objects, advantages and features of the present invention will become apparent to those skilled in the art upon reading this disclosure in combination with drawings wherein like numerals refer to like components throughout.